Sickle Cell Disease (SCD) impairs oxygen transport to tissue and causes endothelial injury. Thus, therapeutic interventions aim to improve both, but there is an unmet need for biomarkers to determine when intervention is necessary and evaluate the effectiveness of the chosen intervention in individual patients. We propose to monitor SCD and its treatment through their impact on cerebral hemodynamics, as the brain is one of the most vulnerable and consequential targets of the disease. Specifically, we will optimize quantitative magnetic resonance imaging (MRI) and advanced optical spectroscopy techniques (frequency-domain near-infrared and diffuse correlation spectroscopies; FDNIRS-DCS) to monitor 1) cerebral oxygen transport with measures of cerebral blood flow (CBF), cerebral oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO2) and 2) endothelial function with cerebrovascular reactivity (CVR). In this 90-day proposal we will recruit three SCD patients (one untreated, one treated with gene therapy targeting BCL11A (?Pilot and Feasibility Study of Hematopoietic Stem Cell Gene Transfer for Sickle Cell Disease (IND # 17660; NCT # 03282656)) and one undergoing chronic transfusion therapy) for a feasibility study. We aim to show we can recruit diverse SCD patients and perform these MRI and FDNIRS-DCS studies. In the planned subsequent full proposal, we will aim to monitor baseline cerebral oxygen transport and CVR, as well as changes that occur with treatment (transfusion or genetic therapy to induce fetal hemoglobin) and assess hemoglobinopathy patients with known genotypes and phenotypes. The ultimate goal is to demonstrate the potential of our monitoring approach to select individual SCD subjects for interventions and evaluate individual responses to treatment. Success will help justify inclusion of these modalities in ongoing and future clinical trials of novel SCD therapies.